The objective of this proposed program project is to continue a coordinated multidisciplinary program of research in clinical pharmacology. The research will be directed towards a systematic elucidation of the pharmacokinetics, metabolism and pharmacologic activity of commonly used drugs and their metabolites, an area frequently negelcted by the private sector because financial incentives are lacking. The seven projects detailed in the application should provide useful informaion about the pharmacologically active metabolite of procainamide, N-acetylprocainamide (NAPA), and about phenytoin, both important and widely used drugs with which this research group has a past record of research productivity and the capability to make further useful contributions. In addition, our research should demonstrate versatile new methodology for investigating the pharmacokinetics of drug effect, the application of pharmacokinetics to drug dialysis, and the use of stable isotope and pharmacokinetic techniques to study drug bioavailability and metabolism. In additon, we propose to use hemodynamic studies and non-invasive monitoring to evaluate the pharmacologic effects of NAPA. Our preliminary results with patients on long-term NAPA therapy indicate that it is probably an oversimplification to think of antiarrhythmic drugs as acting exclusively to suppress disordered cardiac rhythmicity. By combining in this project three investigators with special expertise in clinical pharmacokinetics (Dr. Atkinson), cardiovascular physiology and pharmacology (Dr. Lertora), and in drug metabolism and synthetic and analytical chemistry (Dr. Thenot), we believe that we have achieved the critical mass necessary for in-depth research in the field of clinical pharmacology. At the same time, by including only three project leaders all located in a central core facility, we feel that we have retained operating efficiency and the potential for close, meaningful collaboration.